The present application was originally disclosed in U.S. Provisional Patent Application No. 60/278,141, filed on Mar. 23, 2001, and in Patent Cooperation Treaty application, International Application No. PCT/US02/09416, filed on Mar. 25, 2002. Priority is hereby claimed to those patent applications.
The present invention relates generally to a treatment for viruses, and more specifically to a method that uses a hyperbaric chamber to treat persons infected with viruses such as HIV.
Acquired Immune Deficiency Syndrome (AIDS) is a specific group of diseases or conditions that result from suppression of the immune system related to infection with the Human Immunodeficiency Virus (HIV). A person infected with. HIV gradually loses immune function along with certain immune cells called CD4 T-lymphocytes or CD4 T-cells, causing the infected person to become vulnerable to pneumonia, fungus infections, and other common ailments. When the body loses its immune function, a clinical syndrome develops over time and eventually results in death due to opportunistic infections or cancers. A clinical syndrome is characterized by a group of various illnesses that together characterize a disease. Opportunistic infections are infections by organisms that do not normally cause disease except in people whose immune systems have been greatly weakened.
Infection with HIV does not necessarily mean that a person has AIDS, although people who are HIV-positive are often mistakenly said to have AIDS. The progression from the point of HIV infection to the clinical diseases that define AIDS may take six to ten years or more. This progression can be monitored using surrogate markers (laboratory data that correspond to the various stages of disease progression) or clinical endpoints (illnesses associated with more advanced disease). Surrogate markers for the various stages of HIV infection include the declining number of CD4 T-cells, the major type of white blood cell lost because of HIV infection. In general, the lower the infected person's CD4 T-cell count, the weaker the person's immune system and the more advanced the disease state.
Within one to three weeks after infection with HIV, most people experience nonspecific flu-like symptoms such as fever, headache, skin rash, tender lymph nodes, and a vague feeling of discomfort. These symptoms last about one to two weeks. During this phase, known as the acute retroviral syndrome phase, HIV reproduces to very high concentrations in the blood, mutates (changes its genetic nature) frequently, circulates through the blood, and establishes infections throughout the body, especially in the lymphoid organs. The infected person's CD4 T-cell count falls briefly but then returns to near normal levels as the person's immune system responds to the infection. Individuals are thought to be highly infectious during this phase.
Following the acute retroviral syndrome phase, infected individuals enter a prolonged asymptomatic phase—a symptom-free phase that can last ten years or more. Persons with HIV remain in good health during this period, with levels of CD4 T-cells ranging from low to normal (500 to 750 cells per cubic mm of blood). Nevertheless, HIV continues to replicate during the asymptomatic phase, causing progressive destruction of the immune system. Eventually, the immune system weakens to the point that the person enters the early symptomatic phase. This phase can last from a few months to several years and is characterized by rapidly falling levels of CD4 T-cells (500 to 200 cells per cubic mm of blood) and opportunistic infections that are not life threatening.
During the symptomatic phase, the infected person experiences the extensive immune destruction and serious illness that characterize the late symptomatic phase. This phase can also last from a few months to years, and the affected individual may have CD4 T-cell levels below 200 per cubic mm of blood along with certain opportunistic infections that define AIDS. A wasting syndrome of progressive weight loss and debilitating fatigue occurs in a large proportion of people in this stage. The immune system is in a state of severe failure. The person eventually enters the advanced AIDS phase, in which CD4 T-cell numbers are below 50 per cubic mm of blood. Death due to severe life-threatening opportunistic infections and cancers usually occurs within one to two years.
Researchers have known since 1984 that HIV enters human cells by binding with a receptor protein known as CD4, located on human immune-cell surfaces. HIV carries on its surface a viral protein known as gp120, which specifically recognizes and binds to the CD4 protein molecules on the outer surface of human immune cells. Any human cell that has the correct binding molecules on its surface is a potential target for HIV infection. However, it is the specific class of human white blood cells called CD4 T-cells that are most affected by HIV because these cells have high concentrations of the CD4 molecule on their outer surfaces. HIV replication in CD4 T-cells can kill the cells directly; however, the cells also may be killed or rendered dysfunctional by indirect means without ever having been infected with HIV. CD4 T-cells are critical in the normal immune system because they help other types of immune cells respond to invading organisms. As CD4 T-cells are specifically killed during HIV infection, no help is available for immune responses. General immune system failure results, permitting the opportunistic infections and cancers that characterize clinical AIDS.
The Centers for Disease Control and Prevention (CDC) in Atlanta, Ga., has established an authoritative definition for the diagnosis of AIDS. In an HIV-positive individual, the CD4 T-cell count must be below 200 cells per cubic mm of blood, or there must be the clinical appearance of an initial AIDS-defining opportunistic infection, such as PCP (Pneumocystis Carinii Pneumonia), oral candidiasis (thrush), pulmonary tuberculosis, or invasive cervical carcinoma (cancer of the cervix in women).
Traditional treatments for AIDS include antiviral drugs that attack HIV by exploiting vulnerable spots in the viral replication cycle. One target is the process of reverse transcription—that is, the conversion of the viral ribonucleic acid (RNA) into deoxyribonucleic acid (DNA)—that HIV must undergo to be infectious. Reverse transcription is a process unique to retroviruses and is performed by the viral enzyme reverse transcriptase (RT). One class of anti-HIV drugs, known as nucleosides, are all RT inhibitors. Five nucleosides are currently licensed by the U.S. Food and Drug Administration (FDA): zidovudine (Retrovir, AZT), didanosine (Videx, ddl), zalcitabine (Hivid, ddC), stavudine (Zerit, d4T), and lamivudine (Epivir, 3TC). These drugs work as DNA-chain terminators. Because the drug appears to be a normal nucleotide base (the building block of DNA), the RT enzyme mistakenly inserts the drug into the growing viral DNA chain. Once the drug is inserted, no additional DNA bases can be added, and therefore viral DNA synthesis is terminated. Although the nucleosides are more likely to interact with the viral RT enzyme, they also can be incorporated by the enzyme responsible for normal cellular DNA synthesis in the person receiving the drug, leading to toxicity (poisoning) and side effects. Such drug incorporation is usually observed in rapidly dividing cell types, such as the cells of the bone marrow, spongy tissue filling the cavities within bones.
Another problem with traditional treatments is the emergence of drug-resistant forms of HIV in people receiving these drugs. Studies on early treatment of HIV infection with AZT have presented contradictory results as to whether such early treatment prolongs life. Because HIV replicates rapidly and mutates frequently during the earliest period of infection, an HIV-infected person carries many different strains of HIV, some of which may be drug-resistant. The limited variety of HIV in the early stage is thought to make it more susceptible to AZT and related drugs. Although RT inhibitors were never considered a cure for HIV infection, it was hoped that they would slow the progression of AIDS, and AZT has been shown effective in reducing HIV transmission from pregnant women to their babies. However, the clinical benefit of RT inhibitors when used alone has been largely disappointing; they have extended the lives of people with AIDS by only about six months.
Another traditional treatment for AIDS is a class of anti-HIV drugs known as protease inhibitors, approved by the FDA in December 1995. Protease inhibitors work by crippling a key viral enzyme called protease, which is vital to the reproduction of HIV in the later stages of its replication cycle. After HIV replicates—that is, makes copies of its own protein components—these proteins must be cut to specific sizes before they can assemble into a mature virus. Protease is responsible for trimming the new HIV proteins to their required dimensions. When protease is blocked—or inhibited—the proteins are not cut and the defective HIV cannot infect new cells. The first protease inhibitor drug, saquinavir (Invirase), was approved for use in combination with nucleoside drugs such as AZT. In March 1996 two additional drugs, ritonavir (Norvir) and indinavir (Crivaxin), were rapidly approved for use alone or in combination with nucleosides. A fourth drug, nelfinavir (Viracept), was approved by the FDA in March 1997 for both adult and child use. Preliminary results from American and European studies indicate that these drugs cause dramatic increases in the number of CD4 T-cells and decreases in the amount of virus in the blood. These results are about two to three times more powerful than those seen with the nucleoside drugs. Researchers cautioned that new studies also show that HIV can quickly develop resistance to these new drugs, at least when they are used alone. However, researchers suspect that the resistance can be delayed when the agents are combined with other anti-HIV drugs—for example, the nucleosides. The most effective treatment against HIV is currently considered to be a combination of three drugs taken together—two nucleoside RT inhibitors and one protease inhibitor. Although these drug combinations may cause severe side effects (such as diarrhea, abdominal cramps, and anemia), when taken properly they can reduce blood levels of the virus to undetectable levels. Each drug must be taken according to specific guidelines, however, and one missed dose can allow the virus to quickly mutate to a strain that resists the drugs. These drug combinations can also consist of two nucleoside RT inhibitors and one non-nucleoside RT inhibitor, a new class of anti-HIV drug first recommended for approval by the FDA in June 1996. These drugs work similarly to nucleoside RT inhibitors in that they bind to the HIV reverse transcriptase enzyme. However, they do not compete with other nucleosides for binding sites. The first drug of this type to be developed was nevirapine (Viramune), which was approved by the FDA in April 1997. A second non-nucleoside RT inhibitor, delavirdine (Rescriptin), is currently available only in test settings. Both drugs are effective only when taken with nucleoside RT inhibitors and they should not be used with protease inhibitors. “Acquired Immune Deficiency Syndrome,” Microsoft Encarta 98 Encyclopedia, 1993-1997.
The preferred treatment for viruses such as HIV, disclosed in this application, involves the use of a hyperbaric chamber. Hyperbaric chambers are specialized enclosures that can be pressurized to greater than 1 atmosphere; the atmospheric pressure at sea level. Hyperbaric chambers are perhaps best known as being a cure for the bends; a condition that strikes SCUBA divers when they rise to the surface too fast. Pressure on underwater divers doubles at a depth of approximately 30 feet. The increased pressure of each gas component, which the diver is breathing, at depth means that more of each gas will dissolve into the blood and body tissues, a physical effect predicted by Henry's Law, which states that the amount of gas dissolving into any liquid or tissue with which it is in contact is proportional to the partial pressure of that gas. Inhaled gases are in close contact with blood entering the lungs. Hence, the greater the partial pressure of any inhaled gas, the more that gas will diffuse into the blood.
Unlike oxygen and carbon dioxide, nitrogen (N2) is inert; it is not metabolized by the body. At sea level the amount of N2 inhaled and exhaled is the same. This is not the case for O2 and CO2, which are not inert gases but instead participate in metabolism; as a result less O2 is exhaled than inhaled, and more CO2 is exhaled than inhaled. When breathing compressed air at depth, more gas molecules of air are inhaled because the air is at a higher pressure, and hence denser, than at sea level. Both the pressure and amount of inhaled nitrogen and oxygen are greater at depth than at sea level. Most of the extra oxygen is metabolized and doesn't pose any problem at recreational depths. But the extra nitrogen that is inhaled has nowhere to go but into the blood and tissues, where it is stays in the gas phase (“dissolved”) at the higher pressure, until the ambient pressure is reduced; then it starts to dissolve back out, and is excreted in the exhaled air. Two important problems relate to the increased quantity and pressure of nitrogen from inhaling compressed air; nitrogen narcosis and decompression sickness. Although both problems are related to too much nitrogen, they are distinct. Nitrogen narcosis is a function of the increased pressure of the gas and is only a problem as tong as that pressure remains elevated. Thus nitrogen narcosis is solely a function of depth. Because the problem is related only to depth, it can be cured by ascent or reduction in pressure.
Decompression sickness (DCS) is not due to the pressure of nitrogen at depth per se, but instead to the formation of bubbles as dissolved nitrogen comes out of the tissues with ascent. Since bubble formation is in part related to the total amount of nitrogen in the tissues, the dive time or time at pressure is important (the longer the dive, the more nitrogen enters the tissues, up to a point). Thus DCS is a function of depth and duration of the dive and, at least among recreational divers, is a far more common problem than nitrogen narcosis. Unlike nitrogen narcosis, DCS can lead to permanent physical impairment. In 1878 Paul Bert, an eminent French physiologist, published his classic work Le Pression Barometrique, in which he recommended slow ascent in order to prevent the bends. Over the next decade “Caisson Disease”, or DCS, became a recognized malady, and slow ascent from the caisson's high pressure was accepted as the method of prevention. The symptoms of DCS are especially apt to come on if a change from a high pressure environment to ordinary atmospheric pressure is quickly made. They may supervene immediately on leaving the high pressure environment, or they may be delayed for several hours in the mildest form there are simply pains about the knees and in the legs, often of great severity, and occurring in paroxysms. Abdominal pain and vomiting are not uncommon. The legs may be tender to the touch, and the patient may walk with a stiff gait. Dizziness and headache may accompany these neuralgic symptoms, or may occur alone. In the severe form of DCS there is paralysis both of motion and sensation, usually paraplegia (paralysis below the trunk) but the paralysis may be general, involving the trunk and arms. In the most extreme instances the patient rapidly becomes comatose and death occurs in a few hours. The explanation of this condition is still not fully understood. It has been suggested that the symptoms are due to the liberation in the spinal cord of bubbles of nitrogen which have been absorbed by the blood under the high pressure. A large majority of the cases recover. The severe neuralgic pains often require morphine. Inhalations of oxygen and the use of compressed air have been advised. When paraplegia develops the treatment is similar to that of other forms. Microsoft Encarta® 98 Encyclopedia. 1993-1997 Microsoft Corporation.
Decompression sickness (DCS) arises when excess nitrogen leaving tissue forms bubbles large enough to cause symptoms. Size of bubbles is important, since small bubbles can often be found in divers with no symptoms. Detection of bubbles is commonly accomplished with Doppler ultrasound. DCS arises when the pressure gradient for nitrogen leaving the tissues is so great that large bubbles form, probably by coalescence of many smaller bubbles. Large bubbles within tissues and the circulation system cause the symptoms and signs of decompression sickness. When nitrogen bubbles leave the tissues they first enter capillaries and then the veins (venous circulation). Nitrogen bubbles travel in the venous circulation to the lungs, but then are trapped in the lung capillaries because the bubbles are larger than the tiny diameter of the capillaries. Once trapped, the bubbles break up and the nitrogen gas is exhaled. As a result of being trapped and exhaled, the bubbles do not enter the arterial circulation. Blockage of blood flow to joints by the bubbles causes pain, which is “the bends.” Blockage of blood flow to nervous tissue can cause paralysis or stroke. Neurologic symptoms are particularly common because nitrogen is highly soluble in fat (five times more than in blood), and dissolves readily in the fatty myelin sheaths that surround nerves. As the diver ascends nitrogen comes out of these nerve sheaths; if too much nitrogen is in these nerve sheaths at the beginning of ascent, bubbles may form and compress nerves even before they enter the venous circulation. Apart from compressing nerves and blocking circulation, bubbles can also set off certain chemical reactions, collectively called an “inflammatory response.” An inflammatory response is marked by release of certain protein compounds. Although this process is poorly understood in decompression sickness, it is important to note that chemical changes do occur in the blood of DCS patients, and that some symptoms are not simply the result of nerve compression or circulation blockage.
The only effective treatment for DCS is recompression in a hyperbaric chamber, and the sooner the better. Hyperbaric chambers can be found in or near most large U.S. cities. All manifestations of DCS are potentially reversible if the victim can be quickly recompressed in a chamber. Recompression squeezes the nitrogen bubbles to a smaller size and allows a slower and safer egress of nitrogen from the tissues. Delay in hyperbaric therapy may result in permanent paralysis. Treatment is recommended even if symptoms abate or clear before the patient reaches the chamber. This is because bubbles may still be present in the circulation, and could lead to a more devastating problem later on.
The present method may use of gases, including air, and anesthetics, such as nitrous oxide, in a hyperbaric chamber. Nitrous oxide was first used as an anesthetic in 1844, by the American dentist Horace Wells. In 1842 the American surgeon Crawford Long successfully used ethyl ether as a general anesthetic during surgery. Many other general anesthetics have since been discovered. Ether has largely been abandoned because of its dangerous side effects and flammability. Some anesthetics, such as barbiturates and halothane, act by depressing the central nervous system, whereas others, such as nitrous oxide and enflurane, induce amnesia and dissociation.
Other gases, besides air, that may be used in the chamber include the Noble Gases, also called inert gases, which consist of six gaseous chemical elements, which are in order of increasing atomic weight, helium, neon, argon, krypton, xenon, and radon. For many years chemists believed that these gases, were inert—that is, that they would not enter into chemical combinations with other elements or compounds because their outermost shells were completely filled with electrons. This is now known not to be true, for at least the three heaviest inert gases—krypton, xenon, and radon. The forces between the outermost electrons of these three elements and their nuclei are diluted by distance and the interference of other electrons. The energy gained in creating a xenon or radon fluoride is greater than the energy required for promotion of the reaction, and the compounds are chemically stable, although xenon fluorides and oxides are powerful oxidizing agents.
As mentioned above, AIDS is almost always fatal within a few years of a significant CD4/CD8 T lymphocyte depression to less than 200. The general concept of the final common pathway for HIV pathogenesis is based on the suppression of CD4/CD8 T lymphocyte ratio. As discussed above, the current best therapeutic approaches to the treatment of AIDS are based on maintaining the CD4/CD8 ratio by preventing HIV replication. Despite these improvements, however, HIV may evolve resistance to all antiretroviral agents. The therapeutic options for patients failing all antiretroviral treatment are very limited and may include only participation in an investigational trial and prophylaxis for opportunistic infections.
There is a need for effective control of T cell responses as a therapeutic strategy for interfering with the pathogenesis of HIV induced immune deficiency. Several groups have demonstrated that AIDS represents the loss of a T cell lymphostasis wherein the decline in CD4 effector cells leads to an immunodeficient state due to an imbalance in CD4/CD8 lymphocyte availability. Based on this, if it were possible to stimulate CD4 T cell recovery and normalize CD4/CD8 ratios, reversing the AIDS-induced suppressor cell dominance, clinical remission could be accomplished. In an attempt to accomplish this goal, research in the present concept based on the biological effects of molecular gases on cell membranes began.